Glucocorticoids influence performance on declarative memory tasks and tasks of memory for emotional information [1-3]. The cognitive effects of exogenous glucocorticoids depend on dose [4, 5], the time period between administration and testing [6], and the time of testing within the diurnal pattern of cortisol secretion [7, 8]. Additionally, glucocorticoid administration can influence mood, and with chronic administration glucocorticoids may lead to development of mania or depression [9-12]. A potential mechanism by which glucocorticoids may influence emotional behavior is via their effects on the neurophysiological activity of the amygdala and prefrontal cortical structures known to participate in emotional processing [13-15]. Human imaging studies indicate that amygdala, ventral medial prefrontal, and other prefrontal cortical areas are activated during tasks requiring processing of affective stimuli [16, 17]. These data converge with lesion analysis and electrophysiological studies performed in humans or experimental animals to indicate that these structures participate in brain circuits that process emotional information [18, 19]. These brain structures contain dense concentrations of glucocorticoid and mineralocorticoid receptor mRNA, glucocorticoid receptors and mineralocorticoid receptors [20-24]. Increased glucocorticoids appear to potentiate activation of the amygdala and affect processing of emotionally laden stimuli based on both experimental animal studies [25, 26] and correlational human studies [27, 28]. The present study investigates the influence of glucocorticoids on the hemodynamic response that occurs while processing emotionally-valenced visual stimuli known to activate the amygdala and anatomically-related areas of the prefrontal cortex (PFC) in healthy humans. Functional magnetic resonance images will be acquired during the performance of tasks that involve viewing emotionally expressive faces both before and following either hydrocortisone (synthetic cortisol) (0.15 mg/kg or 0.45 mg/kg bolus) or placebo administration. The change in the BOLD signal in structures of interest will be compared across high dose cortisol, low dose cortisol and placebo conditions. In addition, the effects of hydrocortisone on relative blood flow in the amygdala and PFC will be assessed using an arterial spin labeling (ASL) technique to measure perfusion [29, 30]. The findings of this study will guide future research into the effects of glucocorticoids on emotional perception in subjects with mood disorders. This project was initiated during the Summer of 2003. The initial data acquisition indicated that a change in study design was necessary. The corresponding amendment to this protocol is now pending before the IRB.